In this issue of American Family Physician, Mayfield1 summarizes recent recommendations of the American Diabetes Association (ADA), which broaden the diagnostic criteria for diabetes mellitus and advocate routine screening. Under the new guidelines,2 the threshold fasting plasma glucose level for the diagnosis of diabetes has been lowered from 140 mg per dL (7.8 mmol per L) to 126 mg per dL (7.0 mmol per L). Screening is recommended every three years, beginning at age 45 (or earlier in high-risk groups).
These recommendations have broad implications. Lowering the diagnostic threshold shifts the definition of diabetes into the central bulge of the bell curve where the glucose level of most Americans falls. Among U.S. adults 40 to 74 years of age who have not been diagnosed with diabetes, 1.9 million have fasting plasma glucose levels of 126 to 140 mg per dL (7.0 to 7.8 mmol per L), which is almost as many as the 2.2 million who have levels over 140 mg per dL (7.8 mmol per L). Under the new guidelines, at least 1 million Americans (and possibly more) with fasting plasma glucose levels of 126 to 140 mg per dL (7.0 to 7.8 mmol per L), who previously would have been told that they had normal (or impaired) glucose tolerance, will now be informed that they harbor a disease.3 This more aggressive policy has strong support among those committed to detecting diabetes earlier and in larger numbers. The new threshold will certainly do this, but clinicians should look closely at the evidence and consider the potential harms before changing their approach to patients.
The evidence used for the new diagnostic criteria is from epidemiologic studies cited by Mayfield1 that show a progressive increase in the risk of complications beginning with fasting plasma glucose levels as low as 110 to 120 mg per dL (6.1 to 6.7 mmol per L). There are three problems with basing the new policy on these data. First, other studies show no increase in risk at these low levels.4 Second, even if risk is increased, the new policy argues that having a risk factor (a mildly elevated fasting plasma glucose level) is tantamount to having a disease. There is wide overlap between healthy persons and persons with diabetes in the fasting plasma glucose range of 126 to 140 mg per dL (7.0 to 7.8 mmol per L). Each year only 1 to 5 percent of persons with impaired glucose tolerance develop manifestations of diabetes.5 After 10 years, most do not have diabetes or have normal results on retesting.5 Even among Native Americans, a population at high-risk for diabetes, the 10-year incidence of renal failure occurring in those with a fasting plasma glucose level of less than 140 mg per dL (7.8 mmol per L) is only 8.4 cases per 1,000 person-years.6 Labeling persons with a fasting plasma glucose level of 126 to 140 mg per dL (7.0 to 7.8 mmol per L) as having diabetes, when most will not develop meaningful disease, is akin to labeling persons with elevated cholesterol levels as having heart disease.
Third, and most important, there is no prospective evidence that correcting these mild elevations improves health. The evidence that does exist is for persons with higher glucose levels. In the Diabetes Control and Complications Trial (DCCT),7 the landmark study showing that glycemic control prevents microvascular complications, patients began treatment with a mean blood glucose level of 234 mg per dL (13.0 mmol per L) and lowered it to a mean of 155 mg per dL (8.6 mmol per L). Whether normalizing fasting plasma glucose levels in the range of 126 to 140 mg per dL (7.0 to 7.8 mmol per L) has a meaningful impact on patient outcomes is unknown.
Even for persons with higher glucose levels, the magnitude of benefit from glycemic control is uncertain. Although the DCCT7 demonstrated an impressive 44 to 76 percent reduction in the risk of microvascular complications in patients with type 1 diabetes mellitus, 95 percent of patients have type 2 diabetes mellitus. Because patients with type 2 diabetes are older and more likely to die of macrovascular complications and because microvascular complications only manifest after years of disease, patients with type 2 diabetes are less likely to live long enough to enjoy the microvascular benefits of glycemic control.
The impressive relative reductions in microvascular complications translate into more modest reductions in absolute risk.For example, given the incidence of renal disease,8 the 44 percent relative reduction in albuminuria reported by the DCCT7 means that 1,695 patient-years of intensive treatment are required to prevent one case of chronic renal failure. Moreover, the proven benefits of glycemic control are for intermediate end points (e.g., albuminuria), not clinical outcomes. The 76 percent reduction in retinopathy reported by the DCCT is for a three-step change on a retinopathy scale, not for improved vision. For every patient in whom an intermediate outcome is prevented, a larger number must be treated to prevent symptomatic disease.
Finally, the degree of glycemic control that yielded the clinical trial results may be difficult to replicate in normal practice. The DCCT7 results were achieved when 44 percent of subjects were able to lower their glycohemoglobin level below 6.1 percent. In actual practice, 60 percent of patients with type 2 diabetes have glycohemoglobin levels of 8 percent or more after two years of insulin therapy.9
The benefits of an earlier diagnosis must also be weighed against potential harms. Having a diagnosis of diabetes introduces labeling effects (e.g., worry, decreased job and insurance eligibility) and starts patients on a taxing regimen of glucose monitoring, physician appointments, lipid screening, urinalyses, and foot and eye examinations. These visits cause inconvenience, work/school absences and out-of-pocket expenses. The diagnosis also labels patients as high risk, routing them into testing protocols if they develop symptoms such as chest pain. Although the first-line treatment for patients with mild fasting blood glucose elevations should be diet and exercise, some physicians may be tempted to prescribe glucose-lowering drugs if levels remain elevated, exposing patients to potential side effects (e.g., hypoglycemia). Given current uncertainties about the health benefits of detecting or correcting a fasting plasma glucose level of 126 to 140 mg per dL (7.0 to 7.8 mmol per L), these patients may be subjected to harm for no appreciable gain.
Finally, physicians should think twice about the ADA recommendation to routinely screen for diabetes. Most evidence-based groups (U.S. Preventive Services Task Force, American Academy of Family Physicians, American College of Physicians, Canadian Task Force on the Periodic Health Examination) do not recommend such screening. The ADA rationale that hyperglycemic persons are at increased risk of future complications is not particularly persuasive. Increased risk does not prove that screened persons benefit from early detection or that benefits outweigh harms. Similarly, the ADA arguments for starting screening at age 45 (because incidence increases at this age) and for recommending a three-year interval (because complications rarely develop sooner) do not prove whether these parameters improve outcomes. Such evidence is necessary before advocating the testing of 80 million Americans and, as the guidelines do, redefining medical, insurance and legal views on what constitutes appropriate care.